Calcium-permeable AMPA receptors govern PV neuron feature selectivity

Abstract

The brain helps us survive by forming internal representations of the external world1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective5. PV interneurons differ from excitatory cells in their neurotransmitter receptor subtypes, including AMPA receptors6,7. While excitatory neurons express calcium-impermeable AMPA receptors containing the GluA2 subunit, PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find a low expression stoichiometry of GluA2 mRNA relative to other subunits in PV interneurons which is conserved across ferrets, rodents, marmosets, and humans, causing abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Sparse CP-AMPAR manipulations demonstrated that this increase was cell-autonomous and could occur well beyond development. Interestingly, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, suggesting that the selectivity of PV interneurons can be altered without drastically changing connectivity. In GluA2 knockout mice, where all AMPARs are calcium-permeable, excitatory neurons showed significantly reduced orientation selectivity, suggesting that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Remarkably, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, indicating that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a novel role of CP-AMPARs in maintaining a low-selectivity sensory representation in PV interneurons and suggest a conserved molecular mechanism that distinguishes the unique synaptic computations of inhibitory and excitatory neurons.

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

“…AAV: AAV2/9-hSyn1-DIO-eGFP-CW3SL ( 45 ) (titer: 1.79 × 10 13 GC/ml) and AAV1.CamKII0.4.Cre.SV40 (https://www.addgene.org/105558/) (titer: 1.6 × 10 9 GC/ml) were injected to bilateral dorsal CA1 (coordinates: AP 1.9 mm; ML 1.6 mm DV 1.2 mm) for 0.5 μl of AAV mixture per each position into C57B6J WT and SynGAP GAP*/GAP* mice (2 months old) to sparsely label the pyramidal neurons. After 9 days of injection, mice were transcardially perfused with PBS followed by fixation solution (4% paraformaldehyde in PBS) under isoflurane anesthesia immediately before decapitation.…”